Process for preparing alkyl 5-alkylisoxazole-3-carboxylate



United States Patent Ofi ice 3,11%,l6d Patented July 28, 1965 3,196,160 PRGCESS FOR PREPARING ALKYL S-ALKYL- EGXAZQLE-3'QARBQXYLATE Kunio Nalragawa, Hyohgo, and Shinzaburo Sunlirnoto,

Osaka, Japan, assignors to Shionogi & Co., Ltd, Osakashi, Japan N Drawing. Filed June 26, 1962, Ser. No. 205,188 Claims priority, application Japan, Nov. 20, 1959, $466,484 15 Claims. (Cl. 260-307) This application is a continuation-in-part of copending application Serial No. 70,372 filed November 21, 1960 (now abandoned).

The present invention relates to a process for preparing alkyl S-alkylisoxazole-3-carboxylate. More particularly, it relates to an improvement in the production of alkyl S-alkylisoxazole-3-carboxylate which is useful as a starting material in the synthesis of sulfa-drugs.

The said isoxazole compound has been heretofore produced by condensing alkyl acylpyruvate with hydroxylamine in acidic medium and esterifying the resulting intermeditae according to a conventional method [Claisenz Ber., 24, 3908 (1891); Ben, 42, 60 (1909). Meltzer et al.: J. Am. Pharm. Assoc, 42, 594 (1953)]. The process, however, yields a mixture of alkyl 5-alkylisoxazole-3- carboxylate and its position isomer, i.e., alkyl 3-allrylisoxazole-S-carboxylate, each in considerable amounts. Therefore, the process is not an economical method for the production of alkyl S-alkylisoxazole-3-carboxylate. Furthermore, it is very difficult to separate each from the mixture thereof according to an ordinary operation such as solvent extraction and distillation, because their properties are very similar to each other. This diificulty is undesirable in view of the use of the said isoxazole compound as a starting material in the manufacture of a medicinal which is especially required to be pure. However, the above defects have been now overcome by the process of the present invention which produces selec tively alkyl 5-alkylisoxazole-3-carboxylate as a main product.

Accordingly, an object of the present invention is to provide a commercial process for producing alkyl 5-alkyl isoxazole-S-carboxylate in a good yield with a high purity. This and other objects and the manner in which they are accomplished will become apparent to those conversant with the art form the following description of the general class of compounds and the several specific examples and methods of obtaining them presented.

The process of the present invention includes two main reactions, i.e., addition and cyclization, and one side reaction, i.e., hydrolysis, and it is representable by the following scheme:

With respect to the above scheme, the following facts have been now discovered by the inventors:

(l) The addition reaction is reversible. The equilibrium between the a-oxirne II and the 'y-oxime ll through alkyl acylpyruvate I is alfected by some reaction conditions. Thus, the equilibrium is mostly affected by the acidity of the reaction medium. It generally proceeds to the left in acidic medium and to the right in alkaline or neutral medium. However, a strongly acidic medium permits the equilibrium to move to the right. The equilibrium needs the presence of water which, however, is inclined to move it to the right side. The equilibrium is also influenced somewhat by heat and a high reaction temperature accelerates its movement to left or right.

(2) The cyclization reaction is not reversible. Both the conversion of the a-oxime 11 into the 3-carboxylate Ill and that of the y-oxime ll into the 5-carboxylate III are accelerated under an acidic condition at a high temperatre but interrupted under a neutral or alkaline condition at a low temperature. However, the former conversion is difiicultly influenced by these conditions in general and sometimes proceeds so fast, subsequent to the addition reaction, that the isolation of the u-oxime II is impossible. On the contrary, the latter conversion is greatly influenced by said conditions and, therefore, the v-oxime II can be readily obtained under a suitably controlled condition.

(3) The hydrolysis reaction is reversible. Both the equilibrium between the S-carboxylate III and the 3-carboxylic acid IV and that between the S-carboxylate HI and the S-carboxylic acid IV are moved downwards in the presence of water and upwards in the presence of an allcanol. These movements are accelerated by heat.

The process of the present invention is based on these discoveries and substantially comprises reacting alkyl acylpyruvate I with hydroxylamine in a suitably acidic and anhydrous medium at a low temperature and recovering alkyl 5-alkylisoxazole-3-carboxylate III from the reaction mixture. There are, however, some critical conditions for the successful accomplishment of the process and these critical conditions are now disclosed in detail below.

A starting material is alkyl .acylpyruvate corresponding to Formula I and another starting material is hydroxylamine hydrochloride (H NOl-I.Hl) or hydroxylamine sulfate (H NOH. /2H S0 Although there are known some salts of hydroxylamine such as hydroxylarnine hydrochloride, hydroxylamine sulfate and hydroxylarnine hydrogen sulfate (H NOHH SOQ, the use of hydroxylamine sulfate is the most preferable, because it affords a suitable acidity to the medium in the course of the reaction without the addition of any other acidic substance. The acidity produced from hydroxylamine hydrogen sulfate is too strong for the production of the 3-carboxylate III and is rather suitable for the by-production of the 'y-oxime -II' and the S-carboxylate III. Although the acidity of hydroxylamine hydrochloride is suitable forthe present reaction, its use is not preferable, when the recovery of the solvent is intended, because the hydrochloric acid produced therefrom renders difficult the purification of the recovered solvent. Hydroxylamine hydrochloride or hydroxylamine sulfate may be employed in an equim-olar or a little excess amount, preferably at a ratio from 1 to 1.3 moles to 1 mole of alkyl acylpyruvate I. As the reaction solvent, there may be employed a lower alkanol such as methanol, ethanol and propanol or its mixture with a water-immiscible inert solvent such as benzene, toluene, xylene and ether. These solvents should be substantially anhydrous, although not necessarily completely water-free. The lower alkanol employed may correspond or not to the alkyl radical (R' in the Formula I) in the ester residue of the. starting alkyl acylpyruvate I. When the lower alkanol does not correspond to the alkyl radical, the exchange of the ester residue may take place simultaneously with the addition reaction and/or the cyclization reaction. The reaction temperature should be lower than 50 C., preferably between 20 C. and 35 C. Under the optimum reaction temperature, the reaction time is usually from 3 to hours. The reaction can proceed at both higher and lower temperature and shorter and longer reaction times, the lower temperature usually requiring a correspondingly longer reaction time. However, the higher temperature undesirably results in the by-production of the S-carboxylate III, the 3-carboxylic acid IV and the S-carboxylic acid IV in considerable amounts.

The reaction mixture includes the 3-carboxylate III as a main product and the 'y-oxime II as an inevitable byproduct. It is greatly advantageous that the elimination of the by-pro-duced 'y oxime II from the reaction mixture can be readily'accomplished by a per se conventional procedure, diiferent from the separation of the 3-carboxylate III and the 5-carboxylate III. Thus, the reaction ixture may be completely neutralized with a basic substance such .as sodium hydroxide, potassium hydroxide, ammonia, pyridine, picoline, dimethylaniline, dimethylamine and diethylamine, preferably using an indicator such :as methyl orange and methyl red, extracted with a waterimmiscible, solvent suchfas benzene, toluene and xylene, the solvent removed from the extract and the residue fractionally distilled to give the 3-carboxylate III in a high purity. Hereupon, the said neutralizaton of the reaction mixture is preferred to be carried out at a temperature lower than 20 C. so as to avoid the side reaction.

The above recovery procedure may be partially changed, when the product is alkyl 5-methylisoxazole-3- carboxylate (R is methyl in the Formula III) contaminated with alkyl v-hydroxyiminoacetylpyruvate (R is methyl in the Formula II). In this case, the 'y-oxime II is unexpectedly soluble in water but the 3-car-boxylate III is not. Accordingly, after the neutralization, the reaction mixture may be shaken with a water-immiscible solvent in the presence of a considerable amount of water whereby the 'y-oxime II is retained in the water layer, followed by the removal of the solvent from the waterimmiscible solvent layer to recover the 3-car boxylate III.

Summarizing the above disclosure, the most preferable procedure of the process may comprise (a) reacting alkyl .acylpyruvate -I (1 mole) with hydroxylamine sulfate (1 to 1.3 moles) in a substantially anhydrous lower alkanolic medium at a temperature between 20 C. and 36 C. for 3 to 5 hours; (b) neutralizing the reaction mixture with a basic substance at .a temperature lower than 20 C.; (c) shaking the neutralized mixture with a water-immiscible solvent in the presence or absence of .a considerable amount of water; (d) removing the solvent from the water-immiscible solvent layer; and, if necessary, (2) distilling fractionally the residue to obtain alkyl .i' alkylisoxazoie-3 carboxylate III in a high purity.

The above process can afford the 3-carboxylate III in a high purity. However, the yield of the product is unsatisfactory, because the y-oxime II by-produced is removed from the reaction mixture without its reconversion into the 3-carboxylate III through alkyl acylpyruvate I and the ot-oxime II. The present invention also includes the improvement in this respect, as hereinafter disclosed.

For the reconversion of the oxime II to the 3-carlboxylate III, the reaction mixture obtained above may be suitably neutralized with a basic substance and heated with refluxing While eliminating the water produced in the course of the reaction. The subsequent treatment of the resulting mixture according to the same recovery procedure as disclosed above gives the 3-carboxylate III in a good yield with a high purity.

In this improved procedure, heating is essential for the conversion of the 'y-oxime II into the 3-carboxylate III. The neutralization is mainly intended to interrupt the production of the irreversibleS-earboxylate III from the reversible 'y-oxime II, when heated. However, a slight acidity is necessary for the-desirable conversion of the woxime II into the irreversible 3-carb-oxylate III. Further, the production of water in the neutralization causes undesirably interrupting the conversion of the 'y-oxime II into the u-oxime II and accelerating the hydrolysis of the once-produced 3-carboxylate III to the 3-carboxylic acid IV. Accordingly, the reaction mixture should be neutralized with a suitable amount of the basic substance, which does not produce water in the neutralization, such as gaseous ammonia, pyridine, picoline and dimethy-laniline. The amount and kind of basic substance used depends upon the character of the acid produced from the salt of hydroxylamine used as the starting material. For instance, when hydroxylamine sulfate is employed as the starting material, the amount of the basic substance is suitably from 0.8 to 1.8 moles, preferably 1.2 to 1.4 moles, er 1 mole of the sulfuric acid. For the removal of the water produced in the reaction, azeotropic distillation is preferably adopted, because the essential heating can be simultaneously attained. Thus, the neutralized mixture may be distilled in the presence of an inert organic solvent, which is immiscible with water in liquid phase but can form an azeotro-pc mixture with water in vapor phase, as an entrainer. For removing water effectively under a mild condition, it is preferred to employ such solvent .as is contained at a small ratio in the azeotropic mixture of which the azeotropic temperature is relatively low. Although the amount of the solvent to be added depends on the kind of the same, one-twentieth to one-thirtieth of the theoretical amount may be enough, because the solvent is repeatedly used by returning to the reaction mixture after its separation from the azeotropic mixture in liquid phase. The solvent may be added at any time prior to the azeotropic distillation, but the addition is ordinarily made at the start of the process, i.e., the addition reaction. As the solvent, there may be used for example benzene, toluene, xylene and the like.

As the result of the azeotropic distillation, there is us- --ua1ly obtained the mixture containing only the H-carboxwherein R and R each has the same significance as designated above and R is a lower alkyl radical corresponding to the lower alkanol used as the reaction solvent. The iminoether Ila is assumed to be produced by the reaction of the OL-OXIII16 H with a lower alkanol and can be isolated from the mixture in a per se conventional manner such as distillation. The iminoether IIa can be also converted into the 3-carboxylate III by heating with an acidic substance such as sulfuric acid and hydrochloric acid in a lower alkanolic medium. As the reaction solvent, there may be. employed a lower alkanol such as methanol, ethanol and propanol or its mixture with a water-immiscible inert solvent such as benzene, toluene, xylene and ether. The reaction may be carried out at a relatively low temperature around 30 to 40 C. However, when such a large amount of water as causes the hydrolysis of the once-produced 3-carboxylate III to the 3-carboxylic acid IV is present, the reaction should be carried out with an .azeotropic distillation as above. Commerically, the conversion of the iminoether IIa into the 3-carboxylate III may be carried out without its separation from the reaction mixture.

The. recovery of the .B-carboxylate III from the resulting mixture can be readily accomplished by removing the solvent, if necessary, followed by the fractional distillation of the residue.

Thus, a typical procedure of the improved process may comprise (a') reacting alkyl acylpyruvate I (1 mole) with hydroxylamine sulfate (1 to 1.3 moles) in a substantially anhydrous lower alkanolic medium at a temperature between C. and C. for 3 to 5 hours; (b') neutralizing the reaction mixture with a basic substance (0.4 to 1.2 moles) which does not produce Water in the neutralization; (c') heating the neutralized mixture in the presence of a Water-immiscible solvent with refluxing whereby water is azeotropic-ally removed; (d) removing the solvent from the resulting mixture; and, if necessary (e') distilling the residue fractionally to obtain alkyl 5- alkyiisoxazole-3-carboxylate III in a good yield with a high purity. When the iminoether Ha is present in the reaction mixture of the step (c'), the step (c") wherein the resulting mixture is again subjected to the azeotropic distillation in the presence of an acidic substance should be performed between the step (c) and the step (d').

The products obtained by the process of the present invention are useful as intermediates in the synthesis of snlfa-drugs. For instance, ethyl 5-methylisoxazole-3-carboxylate (R is methyl and R is ethyl in the Formula 111) is employed for the production of 3-sulfanilamido-5- methylisoxazole [U.S. Patent 2,888,455] according to the following scheme:

I I C O O C2H5 Animation NH 7 i 3 CIL 0 UV 0 Hoirnnnn Reaction No.0 01 111 NaOH C113 0 Condensation l' olsot- NHCO ona in pyridine \Ins o \THC 0 on 1 g-\ s 3 I liq T/ Hydrolysis I 1. O/ NaOH n the similar manner, the other products can be used for the reduction of the corresponding lsulfanilamido-S- alley soxazoles.

The following examples illustrate presently preferred methods of carrying out the present invention.

In these examples, the abbreviations have the following significances: g., gr rn(s); ml., rnillilitre(s); C., degrees Centigrade. Other abbreviations have conventional significances.

Example 1 Ethyl acetylpyruvate (79.0 g.) and hydroxylamine sulfate (45.1 g.) are stirred in a mixture of 99% ethanol (145 ml.) and benzene (70 g.) for 4 hours at a temperature between 3 C. and 32 C. The resultant mixture is neutralized with 28% aqueous ammonia at a temperature between 15 C. and 20 C. using methyl orange as an indicator. The neutralized mixture is extracted with benzene. The benzene layer is washed with wate Removing the solvent from the resulting benzene layer, the residue is distilled under reduced pressure to yield ethyl S-methylisoxazole-3-carboxylate (57.7 g.) as a fraction boiling at 105 C./ 10 mm. l-lg, which contains only 1% of ethyl 3-methylisoxazole-5-carboxylate.

Example 2 To a solution of ethyl propionylpyruvate (43.0 g.) in 99% ethanol (60 ml), there is added hydroxylamine sulfate (22.6 g.) while stirring. The resultant mixture is stirred for 5 hours at a temperature between 20 C. and 25 C., and then neutralized with ammonia at a temperature between 10 and 15 C. using methyl orange as an indicator. After removing the solvent at a temperature lower than 50 C., the residue is shaken with a mixture of water (40 ml.) and benzene (40 ml). The benzene layer is Washed with Water, 5% aqueous solution of sodium bicarbonate, and then Water. Removing the solvent from the resulting benzene layer, the oily residue is distilled under reduced pressure to yield ethyl 5-ethylisoxazole-B-corboxylate (26.2 g.) as a fraction boiling at 93 to 95 C./5 mm. H

n 3 1.4555. A233? 239 m (log 613-50).

Analysis.Calcd. for c u o c, 56.80; H, 6.50; N, 8.23; OC H 26.62. Found: C, 57.11; H, 6.66; N, 8.07; oo e 26.32.

Example 3 To a solution of ethyl butyroylpyruvate (46.5 g.) in 99% ethanol (60 ml), there is added hydroxylamine sulfate (2 2.6 g). The resultant mixture is reacted and treated as in Example 2 to yield ethyl 5-propylisoxazole-3- carboxylate (30.0 g.) as a fraction boiling at 103 to 106 C./ 3 mm. Hg.

12%, 1.4554. 122;?240 mp (10g 623.51).

Analysis-Calcd. for C9H13O3N: C, 59.01; H, 7.10; N, 7.65; OC H 24.59. Found: C, 59.19; H, 7.31; N, 7.63; OC H 24.31.

Example 4 To a solution of ethyl isobutyroylpymvate (46.5 g.) in 99% ethanol (60 ml), there is added hydroxylamine sulfate (22.6 g.). The resultant mixture is reacted and treated as in Example 2 to yield ethyl 5-isopropylisoxazole- 3carboxylate (28.0 g.) as a fraction boiling at 96 to 99 C./3 mm. Hg.

vii 1.4535. K1523 2397 my (log 623.51).

Analysis.-Calcd. for C H O N: C, 59.01; H, 7.10; N, 7.65; GC H 24.59. Found: C, 59.00; H, 7.13; N, 7.59; 00 1-1 24.20.

Example 5 To a solution of ethyl pivaloylpyruvate (50.0 g.) in 99% ethanol (70 ml), there is added hydroxylamine sulfate (22.6 g). The resultant mixture is reacted and treated as in Example 2 to yield ethyl 5-tert.-butylisoxazole-3-carboxylate 29.0 g.) as a fraction boiling at 108 to 111 C./5.5 mm. Hg.

nil 1.4525. R321? 240 m (log 623.59).

Analysis.Calcd. for C l-l O Nz C, 60.91; H, 7.61; N, 7.10; OC H 22.84. Found: C, 60.81; H, 7.85; N, 6.98; OC H 22.79.

Example 6 To a solution of ethyl acetylpyruvate (79.0 g.) in a mixture of 99% ethanol (145 ml.) and benzene (70 g.), there is added hydroxylamine sulfate (45.1 g.), and the resultant solution is stirred for 4 hours at about 30 C. Then, the reaction mixture is cooled about 15 to 20 C. and neutralized with gaseous ammonia (5.90 g.). After the addition of benzene (15 g), the resulting mixture is azeotropically distilled to remove Water (42 g.) in 11.5 hours. Removing the solvent from the residual solution, the residue is shaken with a mixture of Water (80 m1.) and benzene (80 g.). The Water layer is extracted with benzene. The benzene extract and the benzene layer are combined together, Washed with 5% aqueous solution of sodium carbonate and then Water, and dried. Removing benzene, there is yielded ethyl 5-methylisoxazole-3-carboxylate (74.0 g.) as a fraction boiling at C./l0 mm. Hg. This product contains 5% of the isomeric compound, ethyl 3-1nethylisoxazole-5-carboxylate.

A mixture of ethyl acetylpyruvate (79.0 g.), hydroxylamine sulfate (45.1 g.), 99% ethanol (145 ml.) and benzene (70 g.) is stirred for 3.0 hours at 30 to 31 C. To the reaction mixture, there is added pyridine (30 g.), and the resultant mixture is azeotropically distilled for 7.5 hours to remove water. Removing the solvent, the residue is extracted with benzene. The benzene extract is washed with aqueous solution of sodium carbonate and then water, and dried. Removing benzene, the residual oil is distilled under reduced pressure to yield ethyl S-methylisOxazoleQ-carboxylate (43 g.) as a fraction boiling at 105 to 106 C ./l0 mm. Hg and ethyl a-ethoxyirnino acetylpyruvate (18.1 g.) as a fraction boiling at 115 to 117 C./ 6 mm. Hg. The elementary analysis of the latter is as follows:

Analysis.-Calcd. for C H NO C, 53.73; H, 7.46; N, 6.97; OC H 44.77. Found: C, 53.63; H, 7.44; N, 6.99; OC H 43.25.

A mixture of ethyl a-ethoxyirninoacetylpyruvate (3.65

g.) in 99% ethanol (14.5 ml.), benzene (7 g.) and suluric acid (2.45 g.) is stirred for 1 hour at 30 to 32 C. Removing the solvent from the reaction mixture, the residue is extracted with benzene. The benzene extract is washed with 5% aqueous solution of sodium carbonate and then water, and dried. Removing benzene, the residual oil is distilled under reduced pressure to yield ethyl 5-methylisoxazole-3-carboxylate.

What is claimed is:

1. Process for preparing alkyl 5-allrylisoxazole-3-carboxylate which comprises reacting alkyl acylpyruvate having the following formula:

' boxylate which comprises reacting alkyl acylpyruvate having the following formula:

R-CO--CH -COCOO-R' wherein R and R each represents a lower alkyl radical with hydroxylamine sulfate at a molar ratio of 1:1 to 1.3 in a substantially anhydrous lower alkanolic medium at a temperature between C. and 35 C., neutralizing the reaction mixture with a basic substance selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonia, pyridine, picoline, dimethylaniline, dimethylamine and diethylamine at a temperature lower than 20 C., shaking the neutralized mixture with a waterimmiscible solvent selected from the group consisting of benzene, toluene and xylene and removing the solvent from the water-immiscible solvent layer to obtain alkyl 5- alkylisoxazole-3-carboxylate.

3. Process for preparing :alkyl 5-alkylisoxazole-3-carboxylate which comprises reacting alkyl acylpyruvate having the following formula:

wherein R and R each represents a lower allryl radical with hydroxylamine sulfate at a molar ratio of 1:1 to 1.3 in a substantially anhydrous lower alkanolic medium at a temperature between 20 C. and 35 C., neutralizing the reaction mixture with a basic substance selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonia, pyridine, picoline, dimethylaniline, dimethylamine and diethylamine at a temperature lower than 20 C., shaking the neutralized mixture with a waterimmiscible solvent selected from the group consisting of benzene, toluene and xylene, removing the solvent 5 from the Water-immiscible solvent layer and distilling fractionally the residue to obtain alkyl 5-alkylisoxazole-3- carboxylate.

4. Process for preparing alkyl 5-alkylisoxazole-3-carboxylate which comprises reacting alkyl acylpyruvate having the following formula:

wherein R and R each represents a lower alkyl radical with hydroxylamine sulfate at a molar ratio of 1:1 to 1.3 in a substantially anhydrous lower alkanolic mediumat a temperature between 20 C., and 35 C., neutralizing the reaction mixture with 'a basic substance which does not produce water in the neutralization and selected from the group consisting of gaseous ammonia, pyridine, picoline and dimethylaniline, at a ratio of 0.8 to 1.8 moles of said basic substance to 1 mole of the sulfuric acid produced from the hydroxylamine sulfate employed above, heating the neutralized mixture in the presence of a water-immiscible solvent selected from the group consisting of benzene, toluene and xylene, with refluxing whereby water is azeotropically removed and removing thesolvent from the resulting mixture to obtain alkyl 5-alkylisoxazole-3- carboxylate.

5. Process for preparing alliyl 5-alkylisoxazole-3-carboxylate which comprises reacting alkyl acylpyruvate having the following formula:

wherein R and R each represents a lower alkyl radical with hydroxylamine sulfate at a molar ratio of 1:1 to 1.3 in a substantially anhydrous lower alkanolic medium at a temperature between 20 C. and 35 C., neutralizing the reaction mixture with a basic substance which does not produce water in the neutralization and selected from the group consisting of gaseous ammonia, pyridine, picoline and dimethylaniline, at a ratio of 0.8 to 1.8 moles of said basic substance to 1 mole of the sulfuric acid produced from the hydroxylamine sulfate employed above, heating the neutralized mixture in the presence of a waterimmiscible solvent selected from the group consisting of benzene, toluene and xylene, with refluxing whereby water is azeotropically removed, removing the solvent from the resulting mixture and distilling the residue fractionally to obtain alkyl 5-alkylisoxazole-3-carboxylate.

6. Process for preparing alkyl 5-alkylisoxazole-3-carboxylate which comprises reacting alkyl acylpyruvate having the following formula:

wherein R and R each represents a lower alkyl radical with hydroxylamine sulfate at a molar ratio of 1:1 to 1.3 in a substantially anhydrous lower alkanolic medium at a temperature between 20 C. and 35 C., neutralizing the reaction mixture with a basic substance which does not produce water in the neutralization andselected from the group consisting of gaseous ammonia, pyridine, picoline and dimethylaniline, at a ratio of 0.8 to 1.8 moles of said basic substance to 1 mole of the sulfuric acid produced from the hydroxylamine sulfate employed above, heating the neutralized mixture in the presence of a waterimmiscible solvent selected from the group consisting of benzene, toluene and xylene, with refluxing whereby water is azeotropically removed, subjecting the resulting mixture again to the azeotropic distillation in the presence of sulfuric acid and recovering the produced alkyl 5- alkylisoxaz0le-3-carboxylate from the resultant mixture.

7. Process for preparing lower alkyl S-rnethylisoxazole- 3-carboxylate which comprises reacting lower alkyl acetylpyruvate with hydroxylamine sulfate at a molar ratio of 1:1 to 1.3 in a substantially anhydrous lower alkanolic medium at a temperature between 20 C. and 35 C. and recovering the produced lower alkyl S-methyl-isoxazole-3-carboxylate from the reaction mixture.

8. Process according to claim 7, wherein the reaction is carried out in an anhydrous inert solvent selected from the group consisting of a lower alkanol and its mixture with a member selected from the group consisting of benzene, toluene and xylene.

9. Process for preparing lower alkyl 5-methylisoxazole- 3-carboxylate which comprises reacting lower alkyl acetylpyruvate with hydroxylamine sulfate at a molar ratio of 1:1 to 1.3 in a substantially anhydrous lower alkanolic medium at a temperature between 20 C. and 35 C., neutralizing the reaction mixture with a basic substance selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonia, pyridine, picoline, dimethylaniline, dimethylamine and diethylamine at a temperature lower than 20 C., shaking the neutralized mixture with a water-immiscible solvent selected from the group consisting of benzene, toluene and xylene, and removing the solvent from the water-immiscible solvent layer to obtain lower alkyl 5-methylisoxazole-3-carboxylate.

10. Process for preparing lower alkyl S-methylisoxazole-3-carboxylate which comprises reacting lower alkyl acetylpyruvate with hydroxylamine sulfate at a molar ratio of 1:1 to 1.3 in a substantially anhydrous lower alkanolic medium at a temperature between 20 C. and 35 C., neutralizing the reaction mixture with a basic substance which does not produce water in the neutralization and selected from the group consisting of gaseous ammonia, pyridine, picoline and dimethylaniline, at a ratio of 0.8 to 1.8 moles of said basic substance to 1 mole of the sulfuric acid produced from the hydroxylamine sulfate employed above, heating the neutralized mixture in the presence of a water-immiscible solvent selected from the group consisting of benzene, toluene and xylene, with refluxing whereby water is azeotropically removed and removing the solvent from the resulting mixture to obtain lower alkyl S-methylisoxazole-B-carboxylate.

11. Process according to claim 10, wherein gaseous ammonia is the neutralizing agent.

12. Process according to claim 10, wherein pyridine is the neutralizing agent.

13. Process according to claim 1), wherein water is azeotropically removed with benzene as an entrainer.

14. Process for preparing lower alkyl S-methylisoxazole-3-carboxylate which comprises reacting lower alkyl acetylpyruvate with hydroxylamine sulfate at a molar ratio of 1:1 to 1.3 in a substantially anhydrous lower alkanolic medium at a temperature between 20 C. and 35 C., neutralizing the reaction mixture with gaseous ammonia at a ratio of 0.8 to 1.8 moles of the latter to 1 mole of the sulfuric acid produced from the hydroxylamine sulfate employed above, heating the neutralized mixture in the presence of benzene with refluxing whereby Water is azeotropically removed and removing the solvent from the resulting mixture to obtain lower alkyl S-methylisoxazole-3-carboxylate.

15. Process for preparing lower alkyl S-methylisoxazole-3-carboxylate which comprises reacting lower alkyl acetylpyruvate with hydroxylamine sulfate at a molar ratio of 1:1 to 1.3 in a substantially anhydrous lower alkanolic medium at a temperature between 20 C. and 35 C., neutralizing the reaction mixture with pyridine at a ratio of 0.8 to 1.8 moles of the latter to 1 mole of the sulfuric acid produced from the hydroxylarnine sulfate employed above, heating the neutralized mixture in the presence of benzene with refluxing whereby water is azeotropically removed and removing the solvent from the resulting mixture to obtain lower alkyl 5-methylisoxazole-3-carboxylate.

References Cited by the Examiner UNITED STATES PATENTS 2,948,734 8/60 Sangrelet 260--295.5

OTHER REFERENCES Elderfield, Heterocyclic Compounds, vol. 5 (New York, 1957), pages 454-8 and 470.

Meltzer, Chem. Abstracts, vol. 49, pp. 1018-9 (1955). Ryan, Chem. Abstracts, vol. 8, page 1107 (1914). Sherwood, Absorption and Extraction (New York, 1937), page 237.

NICHOLAS S. RIZZO, Primary Examiner. 

1. PROCESS FOR PREPARING ALKYL 5-ALKYLISOXAZOLE-3-CARBOXYLATE WHICH COMPRISES REACTING ALKYL ACYLPYRUVATE HAVING THE FOLLOWING FORMULA: 